This is a competing renewal application for a multi-institutional Program Project Grant (PPG) that focuses on cognitive impairment due to small-vessel cerebrovascular disease (s-CVD). The long-term goals of this program Project are to 1) improve our understanding of the pathogenesis of subcortical ischemic vascular dementia (SIVD) and its interactions with Alzheimer's disease (AD), and 2) to develop and validate clinical and imaging markers that inform clinical diagnosis and prognosis. Previous findings from this Project have shown that both SIVD and AD are associated with changes in cerebral cortex, including atrophy, glucose hypometabolism, and loss of n-acetyl aspartate [NAA]. We hypothesize, however, that the mechanisms leading to these cortical and cognitive changes differ in these two disorders. Because s-CVD and Alzheimer disease frequently co-exist in persons over age 65 years, we propose to develop continuous, rather than binary, measures that describe the relative contributions of s-CVD and AD to cognitive impairment. Three Cores and four Projects are built around a prospective longitudinal study design and complementary multi-modal measures of brain structure and function. The Central Coordinating Core (CCC) recruits and follows over 500 subjects representing a spectrum of cognitive impairment attributed to either s-CVD or AD, as well as normal controls. The Imaging Core (Weiner) quantifies volumes of lacunes [L], white matter lesions [WML], cortical gray matter [cGM], and hippocampus [HV] over time. The Pathology Core (Vinters) determines the nature and severity of neurodegenerative, ischemic, and cerebrovascular pathology for each autopsy case. Project 1 (Reed) tests structural-functional-behavioral relationships associated with regional glucose hypometabolism (measured by FDG-PET) in the dorsolateral frontal vs. temporal-parietal lobes. Project 2 (Weiner) tests for differences in brain-metabolic-behavioral relationships in SIVD and AD, using N-acetylaspartate [NAA] and myoinositol from MRSI, as well as perfusion- and diffusion-tensor MR. Project 3 (Chui) seeks the pathological correlates of hippocampal and cortical atrophy, WML, and lacunes, using computerized co-registration of post-mortem brain with in vivo MRI. Project 5 (Mungas) uses multi-variate random effects analyses to model, over time, the neuropsychological and structural MRI correlates of dementia in s-CVD and AD. By integrating multidimensional data obtained using state-of the art methods, we propose to advance understanding of the pathogenesis of cognitive impairment associated with s-CVD and AD and to provide quantitative tools for diagnosis and prognosis.